Although statin therapy is widely used to lower LDL cholesterol levels in patients at high coronary heart disease risk, many individuals are either statin-intolerant or have an inadequate response to statin therapy. Additional therapeutic approaches have been considered to target this population, and the inhibition of the microsomal triglyceride transfer protein (MTP) might hold out significant therapeutic potential. In order to test the tolerability and efficacy of the MTP inhibitor AEGR-733, Sahama et al. performed a double-blind, 12-week trial that included 84 patients randomly assigned to one of the three following groups:1) ezetimibe 10 mg/d 2) AEGR-733 5.0 mg/d for the first 4 weeks, AEGR-733 7.5 mg/d for the next 4 weeks, and AEGR-733 10 mg/d for the last 4 weeks, and 3) ezetimibe 10 mg/d and AEGR-733 administered with the same dose titration. After 12 weeks, patients treated with ezetimibe alone had a mean LDL cholesterol decrease of 20-22%. Patients treated with AEGR-733 alone had a progressive LDL cholesterol decrease of 19% after 4 weeks, 26% at 8 weeks, and 30% at 12 weeks. In patients receiving the combination therapy, the progressive decrease in LDL cholesterol levels was 35%, 38%, and 46%, respectively. Plasma concentrations of apolipoprotein B-containing proteins, including total cholesterol, non-HDL cholesterol, and lipoprotein (a), were similarly reduced by AEGR-733. Altogether, these results suggest that lowering LDL cholesterol with AEGR-733 with or without ezetimibe could represent another therapeutic option for patients unable to reach LDL cholesterol levels with standard therapy. The article was accompanied by an editorial by Tisha R. Joy and Robert A. Hegele who emphasized the importance of testing the efficacy and safety of cholesterol-lowering drugs beyond statins. They suggested that the study by Samaha et al. provides a proof of concept regarding the safety and efficacy of low-dose MTP inhibition. However, several potential safety issues may warrant further investigation. Finally, they stressed the need for hard cardiovascular disease endpoint studies rather than focusing solely on plasma LDL cholesterol levels as a clinical endpoint.
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